Tuesday, December 30, 2008

As I liked to fancy myself as something of a 60s student radical, on becoming a medical student in the early 1970s I vowed not to join the AMA--mostly because that that time it stood squarely against any efforts to provide universal access to health care. More recently, some of my AMA member friends periodically try to persuade me that I could do more good as a critic inside rather than outside the organization and that I should join.

This is one of those times when I am very pleased not to be an AMA member.

Dr. Joseph M. Heyman, chair of the AMA Board of Trustees, has recently spouted off on the issue of selling physicians' prescribing info to the drug companies:

What apparently prompted this comment was the recent action of the US 1st Circuit Court of Appeals, reversing a lower court ruling that prevented implementation of the New Hampshire law that would ban the sale of physician prescribing information. Dr. Heyman personally has no trouble sharing his prescribing info with Pharma, but admits that some of his fellow docs see the issue differently. He therefore thunders against the court ruling, and the New Hampshire law, as threatening "physician choice."

The commentary is basically a long praise of the AMA's Physician Data Restriction Program, begun in 2006. The PDRP is supposed to allow any physician (AMA member or not) to opt out of the organization's current practice of selling identifiers.

Some background--Medical data mining firms currently buy prescription data from pharmacy chains, pharmacy benefit managers, and who knows what else. They take out all the patient identifying data to comply with privacy laws. They then sell this information to drug companies to allow them to carefully target their sales pitches to docs by letting the drug reps know exactly what and how many prescriptions that doc has recently written (for instance, does he prescribe a lot of your company's drug; or does he prescribe a lot of the competitor drug; and when asked by the rep what he prescribes does he tell the truth). These data, however, are useless unless you can turn the code number that identifies the doc who wrote the Rx into a name and address. That's where the AMA comes in-- they maintain a master file of all those code numbers and they sell that list to the data mining companies for many millions of bucks annually, making up a tidy portion of the AMA's annual revenue.

Till 2006, individual docs (besides having no clue that all this was happening behind their backs) had no say in whether the AMA sold their identifying information. With the start of the PDRP, the AMA quite grudingly offered the choice of opting out. Reports from neutral parties were that very few physicians exercised that right to opt out and most docs were unaware that the PDRP was available.

Why do I accuse Dr. Heyman of sleaze? Mainly because of this statement: "The AMA does not collect, license, sell or have access to physician prescribing data. Health care information companies collect and compile physician prescribing data and sell it to pharmaceutical firms. Through licensing agreements with these companies, the AMA can exert influence to offer programs such as PDRP."

This is a pretty slippery assertion. The impression it seems designed to leave with the reader is that the AMA does not profit from the sale of prescribing data and that it can influence the companies that do sell the data only indirectly; but the AMA is so influential that somehow the PDRP works and those companies agree to abide by the request not to release some individual docs' data. Which of course is not quite true. The truth is that the AMA does not directly sell the prescribing data, but they do sell the secret code that you need to understand the prescribing data, and they make a bundle off selling that. (There is a relevant scene in the Marx Brothers movie, A Day at the Races, but that would take me too far afield.) The PDRP works if it does because the AMA has direct control over the data that it does sell, not because it can "exert influence" over the data miners. (Or so all previous accounts from neutral sources have explained.)

Dr. Heyman refers his readers to the AMA's website that describes PDRP in more detail, and that website directs you in turn to a glitzy brochure:

The brochure (almost all photos and hardly any text) seems designed to persuade you of two things--one, physician choice is absolutely essential here and it would be an ethical outrage if that choice were ever taken away; and two, there are tremendous public health benefits to selling the prescribing data. The AMA further promises to launch a new information service to docs allowing them to compare their own prescibing practices to that of their peers. (Which important service you could of course not have access to, if you were so dim-witted as to have opted out via the PDRP.)

AMA critics point out that hardly any legitimate (that is, non-commercial) researcher uses these data as they are simply too expensive to purchase. I would add that in my last 10 years or so in practice, I had virtually all the data I could want on how my prescribing practices compared to other docs in my community through the kindly managed care plans that wanted me to keep my costs down.

I find it interesting that the AMA has elected to identify the sole ethical question related to this issue as physician's freedom of choice. The ethics of assisting the drug industry to make drugs more costly for patients by aggressively marketing physicians to prescribe only expensive brand-name drugs seems irrelevant to them--as does the ethics of the AMA itself profiting handsomely from this practice.

Tuesday, December 23, 2008

For those of you who are sick and tired of my posting about Dr. Charles Nemeroff and his misdeeds, good news--we may finally have reached the effective end of this saga. The quickest way to access the key documents is via Sen. Charles Grassley's website at the Senate Finance Committee:

Under the date "12-22-08" you will see three links, to a letter from Emory University; to a letter from Emory to the NIH; and to a comment by Grassley on both of the above.

Basically, Emory says that it has completed an initial investigation of Dr. Nemeroff and his unreported income from drug companies. The outcomes: He is to resign permanently as chair of Psychiatry; he is to be banned from any NIH study for two years; he is banned from accepting any money for speaking at events other than formal CME programs; and (according to the NIH letter) he is in a number of other ways being put on a very short leash and will be required to have the administration approve virtually his every move in relationship to accepting money or working with industry.

The Emory letter notes that Dr. Nemeroff believes that he was not required to report his speakers' fees under the then-existing Emory policy. He is quoted as expressing regret for his past actions and promising full cooperation with this new regime.

If things are as they appear then one of the most egregious flaunters of ethical propriety in the relationship between medicine and the pharmaceutical industry has at last been laid low.

It's pretty hard to tell from the articles exactly how widespread are the abuses described, as U.S. drug firms, seeking both cheaper and quicker trials of their new drugs to submit for FDA approval, abandon the US for countries like India--despite the fact that most Indians will never be able to afford the drugs that finally complete the trials. The impression given is that the problem is quite severe, because the system is largely unregulated and unsupervised. The FDA is only just now opening an office in India to allow it to do audits of ongoing trials. According to Hundley, bribery and corruption are so widespread at all levels of the Indian health care system, with doctors and hospitals so overextended that patients routinely feel obligated to pay bribes just to get the most basic care, that it is impossible to imagine that so-called ethics review is legitimate. There are numerous accounts of subjects being asked to sign consent forms in languages they cannot read.

One of Hundley's most interesting interviews is with Kamlesh Solanki, a Dalit (untouchable or lowest caste) who previously worked as a human guinea pig for drug trials. The best of these paid him $150, equal to nearly half a year's wages for a farmer in that region of India. He enjoyed luxurious quarters as a guinea pig with air conditioning, TV, and cushy mattresses on the bed. Despite these benefits he gave up the trial business when he came to realize how much more subjects were paid in the US, and after a subject died in a 2002 Phase I trial of an antidepressant. "Do they think we are worth less [than US citizens]?" he asked Hundley.

--Sen. Charles Grassley's (R-IA) campaign to expose corrupt practices at the medicine-pharma interface has netted an interesting internal document from Wyeth--analogous to some ghostwiting-related memos I discussed in HOOKED.

Grassley's team has unearthed a Wyeth memo detailing a campaign to sell its hormone combo Prempro, even after a major study revealed its association with increased breast cancer risk. The memo lists topics, titles, and outlines for a series of articles to be written by the staff of DesignWrite, a medical information company, with the goal of attracting putative academic "authors" for each article and then placing them in journals.

Grassley has demanded information from Wyeth and DesignWrite regarding the so-called authors and payments made to them. Wyeth denies that any of them received any money.

Reactions to this round of charges are interesting. Wyeth accuses Grassley of recycling outdated arguments, saying that besides not being paid, the academic "authors" had full editorial control over the final articles. This is of course the position of deniability that any drug firm can adopt with reference to ghostwriting. The putative author can, of course, exercise editorial control. Most are "too busy" and so elect not to, or to change only a few minor bits of language. Whistleblowers like David Healy have previously revealed how the attempt to actually exert serious editorial control quickly leads to the withdrawal of the invitation to be the "author" or to receive the opportunity in the future.

Of the two "authors" named by Wilson, one, Dr. John Eden, director of the Sydney Monopause Center in Australia, was purported author of an "Editor's Choice" feature in the May 2003 American Journal of Obstetrics and Gynecology, denying that "definitive evidence" existed tying Prempro to breast cancer. Dr. Eden refused any comment for the article. The documents state that the draft manuscript was written by DesignWrite. The journal says it is investigating.

The second named "author" is Dr. Lila E. Nachtigall, director of the Women's Wellness Center at NYU. Dr. Nachtigall denied to Wilson that anyone had written any of her 1000 articles or three books, and denied any recollection of being provided with a draft or outline. (She also suggested that the U.S. Senate had more important things to worry about than to come pestering her.)

My hope is that each of these instances will be investigated to the hilt, and that if any of these academics are found to have actually engaged in ghost-authoring, their respective institutions should make a severe example of them--a penalty notably absent from previous instances of this offense, despite the fact that all agree that ghostwriting is the most inexcusable of all ethical lapses related to Pharma.

Friday, December 19, 2008

I have been trying to follow the Nemeroff saga closely in this blog because it seems that Dr. Charles Nemeroff is a sort of poster child for the extreme versions of the (un)ethical issues I am trying to address here:

Emory told Sen. Grassley that as part of their promised investigation into why Nemeroff seemed to have stuffed his pockets with far more cash than he ever reported to Emory or to the NIH, they discovered that Dr. Nemeroff had not reported some income because it was for talks that he gave that were "CME-like." Presumably this was supposed to mean that the talks were educational and not promotional. Sen. Grassley shot back a 60-page letter noting that none of his legal staff could discover anywhere the term "CME-like" in any policies. He was so unkind as to suggest that maybe Emory made up this term out of whole cloth. He gently hinted that maybe Emory ought to review the legal penalties for making false statements to Congressional investigators.

As Emory and Grassley duke it out, a sidebar mention in the blog post caught my attention, and seems in many ways much more illustrative of the depths to which (some) physician behavor has sunk. WSJ blog had previously reported on a "Dear Me" letter that Nemeroff had written in 2000:

The story of the letter is this-- Nemeroff was then editor of the journal called Depression and Anxiety. I assume this to be a peer reviewed journal as it is indexed in PubMed. Nemeroff said in the "Dear Me" letter that he was paying himself $3000 to write an article for a special supplement the journal was putting out, to celebrate the 5th anniversary of the antidepressant drug Effexor. (Apparently this was a form letter to be sent to all authors of articles in the supplement, and so "Dear Me" was just Nemeroff's shorthard way of saying that he was one of the authors as well as the editor. Maybe the secretary was supposed to type in his name but forgot to.) The records available to the WSJ blog via the Grassley committee then show that Nemeroff cut himself a $3000 check out of a grant fund that the manufacturer of Effexor, Wyeth, had given to Emory.

Now we can talk all day about editorial conflicts of interest, about how Nemeroff as editor could first decide that there should be a special supplement in his journal that was basically nothing but an infomercial for a single drug, then decide in his editor role that he was one of the brilliant authors who should be asked to write an article, and then proceed to pay himself $3000 of company money for writing the article (assuming that it was not ghostwritten on his behalf by company hacks)--all the while failing to report in the journal that any of this was industry funded.

We could talk about all that, but I want to get back to basics here. Is not a medical journal supposed to be, in some distant sort of way, somehow about the science of medicine? About the scientific facts that physicians ought to know to take good care of patients? Do not the authors and editors of journals have some basic duty to promote the quality of medial science? If so, could somebody please explain to me what the bleep the fact that it's the 5th anniversary of a drug have to do with anything that could conceivably be of scientific interest? And how any self-respecting editor or academic physician could write, or any physician could read, an article "celebrating" the anniversary of the drug without puking? Regardless of who pays for it?

Please explain all this to me and then we can talk about conflicts of interest.

Tuesday, December 16, 2008

The e-mail lists have been abuzz with the latest allegations of pharmaceutically linked impropriety. I can't seem to get the full link to appear in this post for some reason (I am actually doing this from a hotel in Beijing--go figure) , but go to www.newsmax.com and search for "Nobel Prize bribery." The allegations are that AstraZeneca stands to gain a lot of sales for its human papillomavirus (HPV) vaccine as a result of the publicity of the discoverers of HPV winning the Nobel Prize, and so via a couple of intermediary PR organizations, it managed to exert financial influence over the prize committee. The Swedish authorities are investigating this as a possible criminal act, though according to the press account the Swedish media have been notably silent on the matter.

Among several good points Don makes is that the study was stopped early because of the supposed success of Crestor in preventing cardiovascular events--despite the very low absolute size of that "success." The early stoppage of trials is becoming a staple in industry-sponsored research, notes Light. The result is that the trial may not have gone on long enough to show the true side effect profile of this drug in an elderly population. If the Kentucky Derby were run like a modern clinical drug trial (if Light is correct about this), it would no longer be a mile-and-a-quarter race. Rather, the race would be declared over at whatever point the drug company's favored horse was ahead.

It's a pretty good bet that either of the two top names mentioned in the blog post, Joshua Sharfstein and Steven Nissen, would be seen as anathema by the drug industry. Therefore the battle over who gets named FDA head will be an excellent barometer of whether the new Congress and White House are positioned to rein in PhRMA power and influence, or whether it is going to be more of the same. (PhRMA hopes for more of the same, as they tilted heavily toward giving campaign contributions to Dems last year just to be prepared for this eventuality.)

The WSJ post mentions Janet Woodcock as a possible compromise interim head of FDA if the politics get nasty and a new permanent commissioner cannot be agreed on right away. I do not know any of these people and in private, Woodcock might be a wonderful person and eager to take the FDA in a new direction. Under the Bush administration, virtually every public statement Woodcock has made that I can recollect offhand has been as a pro-industry apologist. The history of PhRMA influence over legislation is that you seldom see a major debate on the floor of Congress over a measure. Instead, there is great hoopla over some reform (such as allowing imported drugs from Canada to lower prices). Then the measure is sent to committee. Then months and months go by and somehow, everything quietly disappears and it is as if the hoopla never happened. The influence PhRMA likes to wield is usually in the proverbial back room. So if the commissioner appointment seems somehow to disappear, and an interim commissioner stays on longer than was first planned, we'll know that things are working out as PhRMA wanted.

Monday, December 8, 2008

As part of my catch-up campaign I have to go back to another bit of news from last week. The Canadian Association of University Teachers (CAUT) again found it necessary to weigh in on the ongoing dispute between Dr. Nancy Olivieri and the drug firm Apotex:

Following that post (which offers a brief review of the Olivieri case, there being a longer description in HOOKED), I took a fair amount of heat from some Canadian colleagues who happen to be supporters of Dr. Olivieri. I don't expect to take any heat this time around, as according to CAUT, the behavior of Apotex is so egregious as to beggar description.

After a drawn-out legal battle in which Apotex accused Dr. Olivieri of badmouthing their drug, deferiprone, for thalassemia major, and Olivieri accused the company of trying to suppress data showing the drug's serious side effects, an agreement was reached in November 2004, in which each side agreed to stop disparaging the other. Apotex has now taken Olivieri back to court claiming that she violated the agreement.

CAUT has pointed out in its recent statement that Apotex has adopted a definition of "disparage" that seriously threatens academic freedom. According to some of the charges filed by Apotex with the court, Dr. Olivieri disparages them when:

she appears on a panel or gives a lecture to discuss the ethical issues of the relationship between medical research and the pharmaceutical industry, even if she never mentions Apotex or deferiprone by name

anyone else writes about the "Olivieri case" and mentions the charges against Apotex and deferiprone, even if Olivieri had nothing whatever to do with it (I presume according to Apotex, this post is an example of Dr. Olivieri disparaging them, even though she had and has no idea that I am writing this, and she and I have in fact never met or spoken)

I have no independent source besides CAUT to document Apotex's recent bad behavior. But unlike CAUT's earlier report on the Olivieri case, which drew criticism because many of the actors in the drama who disagreed with Olivieri refused to be interviewed by the CAUT investigators while Olivieri supporters all participated, the present statement seems based strictly on legal documents filed with the court. Assuming CAUT's allegations to be generally true, there is no question this time of different points of view among different participants in the case. This would appear to be a baldfaced attempt to muzzle a critic of the pharmaceutical industry.

After several weeks of not all that much happening at the Pharma-Medicine-Ethics interface, things have gotten busy again, to the extent that our fellow bloggers have even scooped us in some cases. Herewith I attempt to catch up.

--about the Cleveland Clinic's plans to create a new portion of their website in which all conflicts of interest of their staff physicians will be publicly reported. The University of Pennsylvania Medical Center reports a similar program. On the industry side, both Merck and Eli Lilly plan to start posting information on all their payments to physicians in 2009.

Abelson suggests that the media embarrassment suffered by large medical centers when previously undisclosed conflicts of interest are outed has led to this nascent movement, along with the investigative interest that Sen. Charles Grassley has shown in exposing high-rolling academic physicians who somehow have neglected to report their conflicts of interest. (See most recent post, http://brodyhooked.blogspot.com/2008/10/could-new-revelations-bring-down.html).

The Cleveland Clinic mentioned in passing that it expects that only a quarter of its physicians will have anything to report on the new website. HOOKED takes the position that disclosure of conflicts of interest is a relatively unsatisfactory substitute for getting rid of the conflicts in the first place. It remains to be seen whether physicians will be less likely to enter into conflicted relationships with industry when they know that the results will be publicly posted.

Turner and colleagues in Portland showed a truly scary degree of publication bias in journal articles about depression--with roughly half the research studies of SSRI antidepressants showing effectiveness and half not, and with virtually all studies that showed effectiveness getting published, and virtually none of those showing no effectiveness getting published. They managed this study by comparing the FDA biostatisticians' independent review of data presented as part of new drug applications, with the eventual publication that resulted (or failed to result) from the research. They also showed that many published studies were "spun" as positive when they had been assessed by the FDA experts as negative; and that the effect sizes reported in the published studies were frequently inflated from those discerned by the FDA review. The major limitation of Turner et al. was that they addressed only one class of drugs, antidepressants. They also included data that are now many years out of date, perhaps not reflecting more recent practices.

A group at UCSF led by Kristin Rising set out to remedy these deficiencies in a new study:

They looked at all new molecular entities approved by the FDA in the years 2001 and 2002, reasoning that this would have given the investigators enough time to publish all studies that were likely to be published. They reviewed the FDA assessments of all efficacy studies submitted by the drug companies as part of those new drug applications, conducting an extensive search to see if that study was ever published. They also compared the primary endpoints and the conclusions of all FDA-submitted studies with what appeared in the resulting publication (for those studies that were published).

The results were in the same general ballpark as what Turner et al. had found for antidepressants, only not quite so dramatically disastrous. Rising et al. found that 78 percent of the studies they looked at were published. A study submitted to the FDA that showed the company's drug to be effective was about 4 times more likely to be published. Between FDA submission and eventual journal publication, a number of primary trial endpoints that did not show the drug favorably got dropped out, and some new primary endpoints that had not been submitted to the FDA were added, in each case showing the drug in a positive light. The statistical significance of some outcomes changed between FDA submission and publication, in each case in a way that favored the drug.

In sum, Rising et al. noted the same shenanighans--multiple changes being made to the study results by the time they were published, if they were published at all, resulting in a drug footprint in the published literature that bore only a tenuous resemblance to the data submitted to the FDA. The basic lesson is that commercial sponsorship of pharmacotherapy trials has made it harder and harder to practice evidence-based medicine, as the "evidence" is routinely altered in such a way as to make drugs look more effective and safer than they are.

Rising et al. note that a number of the shenanighans they detected could have been prevented by the earlier adoption of mandatory trials registries, aso those who believe that this is the answer to commercial sponsorship will be heartened. I argue in HOOKED that registries are a useful first step but that ultimately a bigger firewall between company money and the conduct of clinical trials is needed.

I have objections, much of the time, to the media's present fetish with always including a "personal interest" anecdote in any news story about medicine. In this case, however, the personal angle is essential, so it's highly appropriate that Harris begins with the story of Bruce Hardy of Ruislip, UK, who has metastatic kidney cancer and who might get an average of 6 months' extra survival with Pfizer's new drug, Sutent--at a cost of $54,000.

NICE has decreed that as a general policy matter, Britain's publicly funded National Health Service cannot afford more than about $22,750 to prolong life for 6 months. (We assume that Mr. Hardy does not have the resources to go into Britain's private medical system where he could get whatever he wanted, so long as he paid for it himself or through private insurance.) After stormy protests NICE is reconsidering this policy.

Harris nicely (no pun intended) lays out the dilemma. According to NICE's detractors, this is heartless policymaking. How can you niggle over a few pounds with human lives hanging in the balance? According to NICE's defenders, the problem is not heartless bureaucrats deciding who lives and who dies, or how medicine is practiced--it is heartless drug companies that price their drugs out of reach. (Indeed, now that it's widely known what price limits NICE is willing to work within, drug companies have suddenly discovered that they can price their drugs for the British market lower than they used to.) You can read both sides of the story in this article.

As this blog is not about health policy generally and not about drug pricing, except as it bears on the ethics of medicine's relationship with the drug industry, I'll say no more about NICE, except to agree in passing with those who argue that the US is in deep doo-doo managing health care costs unless we somehow figure a politically viable way to invent our own version of NICE. All I want to comment for purposes of this blog is to note a small gap in Harris's otherwise comprehensive account. He describes the protests from angry oncologists and their patients that are forcing NICE to reconsider the limits they have set on cancer drugs. But he fails to follow the money trail to study how much drug company money is behind these protests. The industry is masterful in using patient advocacy organizations and other supposedly neutral bodies as PR fronts. Just as with the highly publicized controversy when NICE refused to pay for largely ineffective Alzheimer's drugs several years ago, I'd be willing to bet that the supposedly grass-roots protest was largely industry-funded "astroturf."

And, if you want to explore the ethics of NICE's approach to health care rationing, I must recommend the forthcoming book of my long-time colleague, Leonard Fleck of Michigan State University, Just Caring: Health Care Rationing and Democratic Deliberation, due out from Oxford University Press in March 2009.

Wednesday, November 19, 2008

Both in HOOKED and previously on this blog, I have mentioned examples of physicians who attempt to raise warnings about serious adverse reactions from popular drugs, and who are then subject to intimidation by the manufacturer. A recent story by Alicia Mundy in the Wall Street Journal (subscription required for on-line access) shows how far down the food chain this activity extends.

Mundy recounts the case of Dr. Mary Money, an internist in Hagerstown, MD. She and a colleague started noticing diabetics taking Avandia (rosiglitazone) who developed severe cases of congestive heart failure, which often reversed soon after the drug was stopped. Soon after the drug was introduced in 1999-2000, they looked at 85 patients and noted that more than half had developed significant fluid retention, a precursor of congestive heart failure. She alerted the maker of the drug (SmithKline Beecham, which later merged to form GlaxoSmithKline) and tried also to notify the FDA.

She and her colleague got only form letters from the FDA, but received a delegation of SmithKline folks at their local hospital, Washington County Hospital. They soon found that the delegation had no interest in hearing their evidence and had come solely to chew them out for saying incorrect things about their great drug. A consultant who attended by phone accused them of being unable to interpret the echocardiograms that formed part of their diagnostic workup of the patients.

Later, SmithKline executives contacted Washington County's chief of staff and demanded that he make Dr. Money hush up and stop saying bad things about Avandia. (He claims that he refused to go along.)

Subsequently, as evidence mounted that Avandia patients were at increased risk of heart failure, the company was forced to add more stringent warnings to the label, and the WSJ notes that Avandia sales have been falling since a major article on its risks appeared in the New England Journal.

Two things seem instructive about this case. The first is that, no offense to Dr. Money, but she really seems like small potatoes. One does not usually expect a private-practice internist in Hagerstown to sway medical opinion all that much on her lonesome. The fact that the drug company went to all this effort to discredit and intimidate her seems impressive.

The other instructive thing is that GlaxoSmithKline even today is willing to defend its actions. The company told Mundy that they felt completely justified in "correcting" the "inaccuracies" contained in Dr. Money's claims. When a commercial company cannot tell the difference between a scientific exchange of ideas, or a physician's or scientist's rights of free speech for that matter, and its own marketing and sales agenda, we see why medical professionalism requires that physicians put as much open space as possible between themselves and the drug industry.

Some time ago I was asked by a group doing a documentary about problems with psychiatric drugs to do a filmed interview about my research into the drug industry, as summarized in HOOKED.

I was assured at that time that this was an independent project, despite the fact that the documentary group had ties to the Church of Scientology.

I subsequently became better educated about the many underhanded and dishonest methods used by Scientology to attack the practice of psychiatry and the use of psychotropic medications. Readers of this blog will be aware that I have many issues with how psychiatry is often practiced today, but I cannot endorse across-the-board condemnations and certainly cannot endorse positions that are ideologically motivated and not well grounded in medical evidence.

I then contacted the producers of the documentary and asked that my segment be deleted and notified them that I was withdrawing my consent to participate. They refused to accommodate this request.

I am now advised that the documentary, Making a Killing, is being circulated, though I have not seen a copy of it and cannot judge whether any remarks I am quoted as making are accurate or not or are in context or not. The fact that I was included in the film after specifically objecting, and was given no opportunity to fact-check my segment, would seem to indicate that the tactics used by Scientologists in their anti-psychiatry campaign are indeed as dishonest and underhanded as their critics charge.

I regret very much allowing myself to have become involved in this project and would like it to be known that I disown and disapprove of the final product and the way that it has been disseminated.

--that a Federal appeals court 3-judge panel in Boston overturned a ruling of a lower court and upheld the law passed by New Hampshire, forbidding the sale of data on prescriptions written by individual doctors for use by drug reps.

The data-mining giants, IMS Health and Verispan, had brought suit to challenge the law, and efforts to pass similar laws in other states were largely on hold awaiting the outcome of this action.

The data-mining companies had basically two arguments. First, they claimed that the data had other valuable uses such as health services research, apart from their use by drug reps. Second, they claimed a first amendment right of free commercial speech.

The appeals court panel ruled that the state had made its case that there was a direct public benefit of prohibiting the sale of such data. The judges were persuaded by the evidence that these practices led to "the overzealous prescription of more costly brand-name drugs regardless of both the public health consequences and the probable outcome of a sensible cost/benefit analysis." They thus concluded that there was a substantial state interest in prohibiting the sale of data, and no overriding basic right of the companies to sell the data.

The companies are mulling their next legal challenges to the law, and meanwhile, especially with a more friendly administration about to take office in Washington, states considering the passage of such laws will probably be encouraged to do so.

Monday, November 17, 2008

Nature, in its November 13 issue, reported on the lawsuit filed by the firm Biopure against Charles Natanson, an NIH scientist and author of a study published in JAMA that questioned the safety of one of the firm's products.

At issue is the blood substitute Hemopure, a hemoglobin-based blood substitute. Natanson and colleagues looked at clinical trials of five blood substitutes, one of which was Hemopure. They claimed that these products were associated with a 30 percent increase in death, primarily due to heart attack risk. Biopure then sued, claiming that Natanson had made "false and defamatory statements" about Hemopure both in the JAMA article and also in letters he then sent to health officials in the United Kingdom, Greece, and South Africa (countries in which some of the blood substitutes had been approved for sale). Hemopure was initially approved only in South Africa, where the HIV epidemic has seriously restricted the human blood supply; subsequent to the controversy, South Africa withdrew its approval.

In an editorial, Nature attacked Biopure for this attempt to conduct "science by litigation," and noted that however unlikely the suit was to succeed in court, the clear intention was to intimidate scientists from speaking out against commercial products. (As explained in HOOKED, such a suit is sometimes termed a SLAPP suit, designed to have a chilling effect even it it never goes to court at all--in part because of the disparity in financial power between a large firm that can keep a bevy of lawyers on retainer, and the individual scientist who can barely afford legal counsel if named in such a suit.)

And, as the news account in Nature explained, if you want to measure corporate behavior on the Sleaz-o-meter, Biopure wins hands down. Its previous achievements include: the FDA halting a human trial of Hemopure because of safety concerns; three of its executives and the company sued by the US Securities and Exchange Commission for misrepresenting Hemopure's FDA status to investors; and criminal indictment of the company's former head of regulatory affairs for lying about his own health to avoid testifying before the grand jury.

But the main point that I want to make here is that Natanson, very sadly, appears to have invited some of this treatment through his own conflicts of interest. Natanson (who refused requests to be interviewed by the Nature reporter) failed to disclose that he was involved in a provisional patent application for a new technique to make hemoglobin-based blood substitutes safer. He has since amended his conflict-of-interest statement and has withdrawn his name from the final patent application. But one could not blame Biopure if they saw him more as a business competitor and less as a disinterested NIH scientist. Based on the old adage "it takes one to know one," they might well have concluded that Natanson's research methodology in his meta-analysis in JAMA was just as unreliable as their reports of their own research.

So, while I completely concur with Nature's condemnation of Biopure's resorting to a lawsuit to settle what ought to be a scientific question of drug safety, I must also note that scientists need to cleanse themselves of financial conflicts of interest if they wish their findings to be taken seriously.

Saturday, November 15, 2008

When I did my initial post on the JUPITER study (immediately preceding this post), I had not had the benefit of first talking with a true evidence-based-medicine mayvin. I have now just gotten off the phone with Jerry Hoffman of UCLA, who reviewed my post and the attached comments. I thought I had better hurry up and do a new post before my addled brain forgot all of his observations.

Jerry first of all defended Merrill Goozner against some of my skeptical comments about his blog post. Next, Jerry agreed with me that the basic result of JUPITER is to cast more doubt on the "lipid hypothesis" of how statins help in heart disease, and certainly undermine a strategy of widespread testing of cholesterol and trying to achieve a target level of cholesterol by adjusting statin dose.

Jerry concluded by saying that he put JUPITER together with earlier studies in this way. We know that there are basically three groups of folks--high, medium, and low risk for vascular disease. The really high risk people have already had a stroke or heart attack. For them it seems pretty clear that statins help, and that the number needed to treat (NNT), while still on the high side, at least seems to justify the three costs of statin therapy. (These costs are: the monetary cost of these pricey drugs; the known side effects of statins; and the as-yet-unknown side effects among people who may be on the drug for 30-40 years. One reason that the cost-benefit ratio is favorable in the high risk group is that if you already have had a stroke or heart attack, the chances of your hanging around long enough to develop those possible long term side effects becomes quite low.)

Then we have the low-risk people. For them, the NNT is extremely high. It seems hard to show that the costs, in their case, would be low enough to justify these slight benefits.

Finally we come to the moderate-risk group. JUPITER identified a bunch of these folks, who had the elevated C-reactive protein and also were on the older side. Surprise--their NNT turned out to be intermediate between the highest and lowest risk groups. So the question, first, is: does the intermediate NNT justify the still-substantial costs of statin therapy? (This was Goozner's main point.) If this was explained adequately to patients, some might say yes and others would say no.

The second question is trickier and ignoring it was the main defect in my first post. It is true that if you just looked at the people known to have a high CRP test, the NNT is 95 for 2 years. But that is not the best way to look at the data. If a patient comes to you, the doctor, you have a choice of two strategies. You can look at their existing risk factors, place them in a high-or low-risk category, and advise statins or not depending on that risk assessment, using if you want a tool like the Framingham score. Alternatively, you can order a CRP test and then alter your advice to the patient based on whether it is high or normal.

When you consider the true NNT, you cannot just look at those who are already known to have a high CRP. You have to look at the initial population and factor in the uncertainties associated with the test (such as false positives and negatives, etc.) The NNT for the entire strategy (first test, then treat if high) is going to be a higher number than 95 for 2 years to prevent one bad outcome. Jerry's final question is--how much extra value is added by doing the CRP test, compared to just using other knowledge of risk as we would do today? JUPITER did not give us enough data to answer this question. Specifically, it did not tell us how many patients might have been placed on statins anyway due to other risk factors even had the CRP not been done; nor did it tell us how many patients who did not have another reason to be on statins had to be screened with the CRP in order to yield the relatively small percentage of all comers who ended up in the trial.

I will turn Jerry's good observations into a hypothetical patient coming in the door who is perhaps moderate risk for heart disease, and wants to know if he should take a statin and if he should have that new blood test that he heard about on the news. It seems prudent to offer at least three options:

Stay off statins and focus on lifestyle interventions to prevent heart disease--especially exercise--which for all we know have a lower (more favorable) NNT than statins do

Don't do a CRP and prescribe statins, or not, based on other risk variables precisely as one would if the CRP did not exist

Do the CRP and be guided by the results as to whether to give a statin, the cheapest possible one in the lowest reasonable dose (a modified JUPITER protocol)

My point is that all three options make sense to offer the patient. Jerry would add, that if the patient asked which one Jerry would recommend, he's not sure he'd recommend either statin option based on the totality of today's evidence, including JUPITER.

Finally, you might ask--as this blog is not about statins or heart disease prevention, but the pharmaceutical industry and its relationship with medicine, why have I gone off on this long JUPITER tangent? I might reply that we were forced onto this tangent because a major study that got a lot of media play was hampered by obvious conflicts of interest in its sponsorship and authorship (as again, Goozner accurately noted). This is at least the length that one needs to go to, in today's environment, to decide what to believe of what is published, so as to assure that drug company spin does not trump science. The mere fact that the study was discussed at the meeting of the American Heart Association, and published in the New England Journal, is a completely inadequate assurance of scientific reliability, as multiple examples provided in HOOKED attest.

Thursday, November 13, 2008

The JUPITER study, which you have heard about on the news unless you have been in a deep coma this past week, is the sort of thing us Pharma skeptics would love to find fault with. My fellow blogger Merrill Goozner noted its two sins--first, the study was funded by AstraZeneca, maker of the study drug, rosuvastatin (Crestor); second, the first author, Paul Ridker of Harvard, owns a patent on the high-sensitivity test for C-reactive protein, the test that would be widely used if the study results are accepted. This led Goozner to twist himself into pretzels trying to find flaws in the study: http://www.gooznews.com/archives/001243.html

I studied JUPITER and the accompanying editorial in some detail and (while awaiting a better assessment from my friends who know study design and biostatistics better than I do) would offer the view that our pal Gooz went a bit overboard. Still, there is an important lesson here and it is not what the media claimed.

Basically, JUPITER screened about 89,000 patients and found 17,802 of them who met three major inclusion criteria--they had no existing heart disease; they had a normal cholesterol level; and they had an elevated high-sensitivity C-reactive protein test, a test for general bodily inflammation. The subjects were then randomized to the statin drug or a placebo daily. They were supposed to be followed for 4 years but the data monitoring board recommended cessation of the study after 1.9 years because of a significantly lower rate of all major outcomes (heart attack, stroke, unstable angina, need for coronary artery surgery) in the group that got the statin drug.

One point to note is that the JUPITER population was a relatively high-risk because older population, with the median age in each group being 66.

On one point, Gooz got it exactly right. The news media wildly reported that these bad outcomes had been "cut in half" by the statin. In actual fact, while the rate of bad stuff was generally half as much in the statin as in the placebo group, the more accurate statistic, absolute instead of relative risk reduction, was far less impressive. For example, if you added up all the bad outcomes as a composite endpoint, there would be 1.36 bad outcomes per 100 person-years of follow-up in the placebo group and 0.77 per 100 person-years in the statin group. This translates into a number needed to treat (NNT) of 95 over 2 years (that is, you would need to treat 95 patients for 2 years with statins to prevent one bad outcome). It is worth noting that this NNT is quite a bit more favorable than in most previous trials of primary prevention with statins, where it is not unusual to see NNT's in the range of 300 to 400. (A low NNT is good, a high one is bad.)

Another score for JUPITER--the death rate was reduced by statins but not by as much as the other bad outcomes. (There was only about a 20 percent relative risk reduction in deaths vs. the nearly 50 percent relative risk reduction for the other outcomes.) Still, this is very impressive because in many earlier primary prevention trials, while statins reduced the number of heart attacks or strokes, they could not be shown to reduce the overall death rate one bit. (This is partly what has led some to fear that statins increase the risk of other deadly diseases such as cancer at the same time that they reduce cardiac or vascular risks. In JUPITER there was no increase in cancers among the statin group, through the follow-up period was of course very short.)

There was also a very limited downside to taking statins for the duration of the study. The only adverse event that happened more often in the statin group was a new diagnosis of diabetes, and this was only a slight difference (3.0 vs. 2.4 percent). A lot of these subjects were diagnosed at the start with metabolic syndrome so their baseline risk of diabetes was very high.

So, bottom line-- it seem hard to argue that this study is a winner for using statins for primary prevention (before any vascular disease has arisen) in one high-risk population, those with elevated c-reactive protein; and that in turn implies the value of using the CRP test as a routine screening test. The NNT of 95 is quite respectable among primary prevention trials.

The JUPITER authors seem to have been fully aware of the skepticism that would greet their paper due to the obvious conflicts of interest. They went to great lengths to note that AstraZeneca did not even see the unblinded trial data until after the manuscript was submitted for publication. Two committees were said to be completely independent of both the company and the principal investigators--an endpoint adjudication committee and a data monitoring and safety committee. In short, if these statements are all true, the study was squeaky clean despite the commercial sponsorship.

Now I come to the point that the media seems completely to have missed. Skeptics of the widespread use of statins (like yours truly) have for a long time insisted that the bulk of the research literature to date does not support the "lipid hypothesis"--that statins work by lowering "bad cholesterol" levels; and that it is critically important to screen patients by testing their cholesterol, and then doing repeated tests to be sure that the response to statin treatment is a low enough level. We have insisted instead that the research indicates that whether or not statins are good for you depends almost completely on whether you have certain risk factors. The biggest risk factor, and the groups where statins have been shown most clearly to work, is already existing vascular disease (that is, secondary prevention). By contrast, very little benefit from statins has been seen in most primary prevention trials, except in men at high risk in the roughly 40-65 age group, and even there with a very high NNT. Since you don't need a cholesterol test to know if you have those risk factors, we have argued that the massive use of cholesterol screening leads to the inappropriate overuse of statins. Moreover, there is no evidence that hitting a lower target cholesterol level by increasing the statin dose lowers your risk to any significant degree.

One way to summarize all these data is to suggest that it is quite possible that statins prevent heart attacks and strokes, but not by lowering cholesterol. They are known to have an anti-inflammatory effect, and it is thought that inflammation plays a role in turning arterial plaque into a major blockage of a vessel that leads to bad disease. It may be their anti-inflammatory effect and not the lipid-lowering effect that explains why they work in the highest-risk groups.

Well, if this hypothesis was worthy of consideration yesterday, it has now received a huge boost with JUPITER. Based on lipid screening, these subjects did not need any statin. Yet they did better on a statin for primary prevention. They were a very high risk group (mainly due to age) and also had signs suggestive of an inflammatory process.

The media never picked up on this. All the coverage I heard simply took for granted that it was wise to treat elevated cholesterol with statins, so now we had yet another huge group of patients who needed a statin in addition to those with high cholesterol. On NPR (of all places) this morning, I heard a physician quoted that JUPITER showed that we need to reduce levels of cholesterol much lower than anyone had previously realized--when the real message is to test CRP and forget all about cholesterol. Even if the lipid hypothesis of statin treatment is all wet, we still seem completely hooked on it.

Tuesday, October 28, 2008

I hope what I am about to share is a sign of the times. It is very easy to wonder in this line of work--is all the action happening at the level of the leadership of the academic medical center or major organizations like AAMC? Is anything really changing in the trenches--or, as today's political jargon has it, down on Main Street?

I am a member of the American Academy of Family Physicians and as such am automatically enrolled as a member of the state and local chapters of AAFP. When I moved to Texas in 2006, I therefore became a member of the Texas and Galveston County chapters of AAFP. I did not attend meetings of the local chapter for two reasons. First, I was not involved in practice but rather in administration and teaching, and so had met very few of the local family docs. More important, I soon learned from the meeting notices that all their meetings were dinner meetings and were subsidized by drug reps. As a signatory to the No Free Lunch Pledge I could not attend (or at least would have to brown-bag it if I did).

I was therefore very intrigued to receive the notice below today (key point in italics, added):

The Galveston Chapter of the Texas Academy of Family Physicians invites you to:An Organizational MeetingThere is no educational program. We will have a round table discussion of the future of our chapter and the venue, frequency and format of meetings. Drug company sponsorship will probably go away.This is an important decision making meeting.Given that the new PhRMA code of conduct says that "modest" meals will continue as far as the drug companies are concerned, I am not sure exactly why the leadership of the society is certain that drug company sponsorship for meetings will disappear--unless it is because of the tightening of controls over not mixing up education with marketing, so that if CME credit is awarded for the educational presentation, then overt drug company sponsorship will not be allowed.

Nonetheless I pass along this anecdote as perhaps a hint that the times they are a-changin'.

Monday, October 20, 2008

Here's another complicated story that came to light (no pun intended) when some people noted that an entire issue of the Harvard Health Policy Review seemed to have disappeared from the web. One article in that issue was by Donald W. Light and Rebecca N. Warburton and accused the Harvard-based editors of the Journal of Health Economics (JHE) of bias in handling an earlier paper of theirs on the true costs of drug industry research. (Disclosure: I am currently involved with Don Light in co-authoring a couple of manuscripts.)

One of the most widely cited pair of papers, published in the JHE in 1991 and 2003, was by DiMasi et al. of the Tufts Center for the Study of Drug Development. The second paper reached the widely quoted conclusion that it costs the drug industry $800M to develop one new drug, when you count all the failed drugs that have to be investigated along the way. The Tufts center is well known to be funded almost entirely by the drug industry, and the $800M figure has been much repeated in industry-friendly sources.

Light and Warburton wrote a paper criticizing the methods used by DiMasi and colleagues, and also calling atention to how the funding of their center created a conflict of interest in relation to their research. They chose to submit the paper to JHE, on the natural assumption that the journal would find controversy about a previously published paper interesting to their readers.

The editorial board assigned editor Thomas McGuire to the Light-Warburton manuscript. Light and Warburton describe this as an editorial conflict of interest as McGuire had also edited the DiMasi papers and could view the Light-Warburton critique as an attack on his own editorial judgment. (I demur here and wonder if the paper was assigned to McGuire because drug company research might have been his own special area of expertise.)

There then followed a long soap opera of disputes between the authors and McGuire, which is painstakingly detailed in the second Light-Warburton article. Suffice it to say here that McGuire seemed more interested in excising from the manuscript any passage that might offend DiMasi and his Center, than in protecting the intellectual integrity of the exchange of ideas. McGuire also appeared to have sent the Light-Warburton manuscript to DiMasi for comment without notifying the authors of that fact. JHE accepted from DiMasi a long and tangential reply to the charges raised by Light and Warburton, and when the latter two tried to rebut statements in the reply, they found their own rebuttal severely restricted both in length and in content. Finally, when the paper was published on the web, Light and Warburton discovered for the first time that DiMasi and his colleagues had been allowed to append a further response, which they had never seen and to which they had no opportunity to reply. In short, rather than dealing seriously with the charges from Light and Warburton that DiMasi et al. had used inferior methods, JHE gave DiMasi et al. every possible opportunity to restate their own case and to impugn Light and Warburton in the process.

Irked by this evidence of extremely one-sided editorial management, Light and Warburton proceeded to write their paper #2 exposing the conduct of the JHE editors, contrasting their behavior unfavorably to several published codes of ethics for journal editors, and making recommendations for further reforms based on their own sad experience. Their paper #2 was published in the Harvard Health Policy Review, Spring 2008 issue. That entire issue has recently disappeared with no explanation from the periodical's website (according to several fellow Pharma bloggers--see for example the Oct. 20 post on http://www.gooznews.com/).

Sunday, October 19, 2008

What the AMA House of Delegates didn't have the guts, or the good sense, to do back in June, the Wisconsin Medical Society has now done, as noted by several of our fellow blogs. The core language of their recent statement to their members is:

Physicians shall accept no gifts from any provider of products that they prescribe to their patients such as personal items, office supplies, food, travel and time costs, or payment for participation in on-line CME. A complete ban eases the burdens of compliance, biased decision making, and patient distrust.The press release is dated Oct. 16 and can be found at http://www.wisconsinmedicalsociety.org/publications_and_media/press_releases

See how short and sweet it can be when you cut through the garbage and get straight to the point?

Pardon me while I wipe the egg off my face. I recently wrote about the spam comments that this blog had been attracting--that whenever I posted anything about Pfizer or certain key words, a comment would appear that seemed to be a blatant advertisement for their stop-smoking drug Chantix. I charged that the company must have a web-crawler program that was posting these comments automatically on all blogs.

An anonymous individual then appended a comment to that post, noting that the advertised website, which I had not bothered to click on, is not a Pfizer official website but actually a clever look-alike URL designed to make the viewer think it's Pfizer, but actually including a disclaimer in small print. In other words, this blog is being hacked into to advertise, but the people doing it are probably drug counterfeiters, not a legitimate drug company. "Don't you ever check facts?" asked this commentator, not unreasonably.

So I have taken down the original incorrect post and apologize to Pfizer and anyone else concerned. (I know by the way that this post will soon attract another phony "comment" from the web-crawler.)

Friday, October 17, 2008

The Healthy Skepticism listserv recently featured a very insightful and helpful comment from a Down Under pharmacist, Dr. Chris Doecke, of the Royal Adelaide Hospital. Though this blog is not primarily about why drugs cost so much, it is about techniques of drug marketing, so I thought Dr. Doecke's expose of the myths surrounding the term "biologicals" might be helpful to readers:

I also would like to highlight another very common myth that is often promoted in the area of new pharmaceuticals generally, but particularly with cancer treatments. Unfortunately many health professional have also been sucked in that most new drugs are "biologicals". Once said this somehow immediately justifies a $100K per year price tag without further challenge.

The quotes from the BW article were: "Because cancer treatments often consist of complex protein molecules that take years to develop, the drug multinationals left these risky products to small biotech ventures such as ImClone." "And Roche, bowing to pressure from Britain's National Institute for Health & Clinical Excellence (NICE), slashed the price of lung cancer drug Tarceva by $1,200 to $10,830 per four-month course of treatment."

Point one

Tarceva is erlotinib hydrochloride, a fairly simple small synthetic chemical. It is not a protein, it is not complex. It inhibits endogenous receptors in the body to modify physiologic processes (tyrosine kinase activity) just as atenolol inhibits endogenous receptors in the body (beta adrenergic receptors). Erlotinib is presented as a simple oral film coated tablet. We are being duped into linking these simple chemicals with "biologicals" because they are use for cancer treatment. Novartis did exactly the same with imatinib for CML. A$50-75K per year per patient for a simple oral dose form.

Point twoThe fact that a pharmaceutical is a proteins should NOT immediately justify a $100K per year price tag. Most are produced by using a recombinant process via a cell line. Once the process is established, cells simply spew out protein. I simplify a little, but as part of my PhD I produced active protein via recombinant techniques - hence isn't that difficult. Finally we have had recombinant human insulin available for decades at arguably reasonable prices.

In summary, this is a subtle process that we often get sucked into. That is, that everything for cancer is "biological" and that everything biological is rare, complex and expensive. As health practitioners we need to de-bunk these myths at every opportunity.

Thanks to Chris for giving permission to reprint his comment here, and he notes that he will be expanding the discussion for a future edition of the Healthy Skepticism Newsletter.

Tuesday, October 7, 2008

Following up on the previous post, in which I asked what would it take to change the culture of academic medicine so that a Nemeroff phenomenon would become impossible, I think it worth drilling down a bit deeper into the past record of Emory med school's relationship with its chair of psychiatry (who, it is now reported, has temporarily stepped down pending the promised new investigation). My text here is the previously cited NYT article: Gardiner Harris, "Top Psychiatrist Didn't Report Drug Makers' Pay," New York Times, Oct. 4, 2008 (see previous post for link).

Threaded through the account unearthed by Congressional investigators, showing a pattern of underreporting huge payments from drug companies and concealing financial conflicts of interest related to NIH grants, is a record of periodic and ineffectual efforts by Emory to rein in or at least get a grip on Dr. Nemeroff's behavior. Harris notes that in theory, if Nemeroff is found to have violated NIH reporting rules, Emory stands to lose $190M in NIH funding, assuming that the agency suspended all grants, which it hardly ever does.

Emory conducted an investigation of Nemeroff's outside consulting arrangements in 2004. A 14-page report mentioned "serious" and "significant" violations of university procedures regarding conflicts of interest. Harris states that Emory then did nothing in response to that report.

In 2006, Nemeroff had to resign as editor of Neuropsychopharmacology, after the journal published a paper with Nemeroff as first author without disclosing the financial relationship between Nemeroff and the maker of the medical device described glowingly in the paper. (Nemeroff claimed that this was due to a clerical error.) This led according to Harris to a "bitter e-mail exchange" between Nemeroff and an associate dean at Emory, Dr. Claudia Adkison, who referred to the published paper as "a piece of paid marketing."

In both 2004 and 2006, Emory's final concrete action regarding the charges against Nemeroff was to ask that he sign a letter stating that he did not accept more than $10,000 annually from any drug firm, thereby keeping within the NIH-specified limit. Nemeroff cheerfully kept signing all these letters, despite the fact that he was raking in more than $100,000 annually from several firms. (Indeed, Harris reports that he actually signed one such letter while at the Four Seasons Resort in Jackson Hole, where he earned $3000 of what would eventually amount to $170,000 that year from GlaxoSmithKline.) The Emory policy in short seems to have been "ask but don't expect him to tell, and since he didn't tell you, you can claim not to know anything."

The Emory statement in the wake of these new revelations, in addition to Nemeroff "voluntarily" stepping down as chair, is that the university is "working diligently to determine whether our policies have been observed consistently... Dr. Nemeroff has assured us that 'To the best of my knowledge, I have followed the appropriate university regulations concerning financial disclosures.'"

So naturally you might ask: how does it come to be that a chair of a department, who was shown by a university investigation four years ago to be untrustworthy in reporting financial conflicts of interest, is allowed simply to state on his own say-so that he has no conflicts, and the university meekly believes him? The answer may lie in an anonymous comment posted to this blog back in January when I first raised the Nemeroff issue. According to that respondent,who echoed a point of view I have heard from other academic psychiatrists, Nemeroff is pleased to bear the nickname "Boss of Bosses." He has a reputation for wielding tremendous power in psychiatry, especially taking advantage of his leverage with the big drug firms, and is ruthless in attacking those whom he doesn't like or who threaten him. One such event is described in some detail in HOOKED, the hiring and then subsequent firing of David Healy as head of a psychiatric research institute at the University of Toronto, due to Healy saying bad things about Prozac, whose manufacturer, Eli Lilly, was at the time considering a major grant to Toronto. Healy cheerfully sued Toronto and won, meaning that all the correspondence related to the firing is now in the public domain. In HOOKED I focused on Toronto's spineless behavior, but it is also interesting to note that almost certainly, Nemeroff was in the background pulling all the strings that led to Healy's dismissal.

Nemeroff was not shy about displaying his "Boss" side to his true bosses at Emory. He sent a confidential letter to the dean of the medical school at Emory in May 2000, listing the dozen corporate advisory boards in which he sat. He then ticked off the grants and endowments that those firms had paid to the Department of Psychiatry at Emory, and added, "Part of the rationale for [the companies'] funding our faculty in such a manner would be my service on those boards." Translation--you mess with my cozy relationships with these companies, and the industry gravy train to Emory dries up. The threat is only slightly veiled, that should Emory decide to take any serious action against Nemeroff for his unreported conflicts of interest, he could easily jump ship to a more permissive med school, taking a lot of his captive research faculty and all of his industry funding with him.

So now we come to the $64 question (or in Nemeroff's case, the $2.8M question), which is what has to happen to the medical school culture to not allow people like Nemeroff to have it all their own way. The incredibly optimistic answer is that universities and academic medical centers have to grow two pieces of anatomy, of which the one I can say in polite society is a backbone. They need to be willing to stand up to the blackmail and intimidation that a "Boss of Bosses" can throw their way--ideally cutting him off early in his career so that he never accumulates the incredible power that Nemeroff now seems to enjoy.

The more pessimistic answer is, what can you expect now that the post-Bayh-Dole university has declared its allegiance to making money over academic values? On this view, the conflict of interest train left the station a long time ago--some say, all the way back in 1980 when the Bayh-Dole act was passed (see HOOKED). If the university must make its research money from industry to stay afloat, then the unversity's conflict of interest is much bigger than any individual faculty member's conflict of interest, even Nemeroff's. And that assures that the university dare not bite the hand that feeds it, whether the hand is Nemeroff's or Eli Lilly's or GlaxoSmithKline's.

I have never met this person and for all I know he is a delightful human being. I bear him no personal ill will. The problem was that wherever I turned in my research on HOOKED, and the topic of conflicts of interest among academic physicians came up, Dr. Nemeroff seemed to be off the charts. He seemed to be the poster child for all that is wrong with the current cozy arrangements between Pharma and acadmic medicine. (Details in the post above.)

I wondered how it could be the case that Nemeroff seemed to be the Teflon Chair of Psychiatry just as Reagan had famously been the Teflon President--no charges ever stuck to him no matter how egregious the behavior--and was able to pursue his career as a leader of academic psychiatry despite all the embarrassing revelations (which apparently did not bother Emory University one whit).

Well, the stuff may now finally have hit the fan. Danny Carlat in his psychiatry blog:http://carlatpsychiatry.blogspot.com/, reporting on an article in the New York Times (http://www.nytimes.com/2008/10/04/health/policy/04drug.html?_r=3&hp&oref=slogin&oref=slogin&oref=slogin) as well as another in the Wall Street Journal, was soon followed by Integrity in Science Watch. The gist of the new exposes is that Nemeroff reported some tens of thousands of dollars in income from drug companies while in actuality he raked in millions. Specifically, according to Gardiner Harris in the Times, he made $2.8M from 2000-2007 and failed to report at least $1.2M, in the process violating Federal rules as principal investigator on studies for which he had a financial interest in the drug being tested. The new revelations come as a result of Congressional investigations, as part of Sens. Grassley and Kohl's proposal for sunshine legislation. Reportedly, as a result of these articles, Emory has belatedly decided that it needs to investigate Nemeroff.

What happens now will be a good test case for the future of the ethics of academic medicine. The basic issue is this. In today's world, a medical school like Emory looks at all the pluses and minuses of having a guy like Nemeroff as a powerful chair, and decides that the pluses outweigh the minuses. His publication record is stellar (mostly ghostwritten of course), he brings in huge research grants, and people in his specialty all over the world want to kiss the hem of his garments. What has to change, in the regulation and the culture of the academic medical center, so that it becomes a no-brainer that having a guy like this on your faculty is a net loser?

Saturday, September 27, 2008

Among the many things I did not know about blogging when I undertook to set up this blog is that there is a particular species of subhuman beast that attempts to avertise some product or service by posting "comments" on blogs like this one. The typical form is: "This is a very interesting post. Your readers may be interested to know that Phallix, a drug that give men huge erections that last for 3 months, is available for only $9.99 at your local pharmacy."

I have this blog set up to send me an e-mail when a reader posts a comment. Somehow these advertisers appear to know how to bypass that notification system. I do have control as blogger to pemanently eliminate any comments that I wish to, and whenever I discover one of these ads, I do so. (Those are the only comments that I have ever eliminated, as we have been very fortunate in not attracting comments that are full of obscenities, for instance.) However it may be some time between when the ad appears and when I come across it (or as happened in this latest case, when another faithful reader pointed it out to me). In the meantime please forgive this defacement of a blog that aims to provide noncommercial and valid information.

Friday, September 19, 2008

The HOOKED blog has been on a bit of a vacation while we Galveston refugees try to sort out our lives after Hurricane Ike (this particular one at least having the luxury of a hotel room and an Internet connection). Since any good news is welcome at such a time, I will pass along word that this blog appears to have been cited as one of the 100 best health policy blogs:

--appears to be a harsh criticism of the biotech company. Freking shows how Genentech is digging in its heels, refusing even to provide the drugs for a major scientific study, and insisting that no matter how the study turns out, its present pricing structure will not be affected (that is, insisting that patients with wet macular degeneration have to pay $2000 per dose for Lucentis, while Avastin does the same thing when used off label at $60 per dose).

Both drugs target a protein that causes blood vessels in the back of the eye to grow, but Lucentis is a much smaller molecule. It was specifically designed _ at great expense _ to penetrate the retina. This is bull. Lucentis was specifically designed--at very low expense--to be the classic "me too" or "evergreening" drug. It is simply the active portion of the Avastin molecule--just like Nexium is nothing but the active stereoisomer of Prilosec. Of course the active portion of the molecule is going to be smaller than the entire molecule. The company then spun that as an advantage for eye use. At least some retinal specialists believe the opposite--that the larger Avastin molecule stays around longer and so is more effective.

If Genentech's propaganda were true, then the head-to-head study comparing the two drugs, now underway by the National Eye Institute (no thanks to Genetech) would be expected to show the superiority of Lucentis. Genentech has shown us how much it is willing to bet on that outcome, by saying that regardless of the results of the trial, it won't change its pricing policies. Translated into plain English, that means that all the evidence now available internally to Genetech scientists shows that Lucentis is no better than Avastin.

[Krysta] Pellegrino [Genentech spokesperson] said Genentech's pricing for Lucentis reflects the cost of developing the drug, which the FDA approved in June 2006. The development program included a clinical trial involving more than 6,000 patients at a cost of more than $45,000 a patient."It took decades and hundreds of millions of dollars to develop the drug," she said.

More bull, just as above. Drugs are priced based on what the market will bear, not on how much the company spent to develop them. Once you have figured out what portion of a complex molecule is biologically most active, it is a scientific slam-dunk to cleave off that piece of molecule and run it through trials. Genentech miscalculated, as our earlier post showed. They thought they could cow the retinal surgery community into meekly forking over their patients' life savings by threatening them with lawsuits if anyone suffered harm from the off-label prescribing of Avastin. (And by simultaneously flooding their offices with smiling reps pushing Lucentis.) The retinal surgeons, bless them, mostly stuck to their guns and continues to prescribe Avastin off label in large quantities.

This article is an object lesson in how hard health and science reporters have to work to cut through the misinformation that well-heeled companies will spin for them.

Monday, September 8, 2008

This entry is courtesy our friends over at the Integrity in Science Watch, http://www.cspinet.org/integrity/. Their Sept. 8 press release features a rundown of sweetheart deals recently concluded between big drug firms and major universities, headlined by a 5-year, $25M deal between Harvard and GlaxoSmithKline giving GSK first rights to any patents generated by Harvard scientists around stem cell research. Equal numbers of GSK and Harvard reps sit on the steering committee to oversee this process. Similar deals listed by Integrity include UC-Santa Barbara, Cal Tech, MIT, U Mass, and Columbia all joining forces with AstraZeneca, and I previously blogged about UNC pretty much selling its school of public health to a commercial CRO (http://brodyhooked.blogspot.com/2008/09/cros-how-independent-really.html).

Perhaps the most intriguing part of the Integrity post is this comment: The drug industry is increasingly turning to campus-based researchers to supplement its own lagging research and development efforts, which have fallen on hard times. The number of new drugs coming out of industry labs and approved by the Food and Drug Administration is at record-low levels.

This analysis tends to confirm a trend that I suggested in HOOKED. It is really interesting that the assembly-line, merger-mania model of industrial research that the industry has favored heavily for the past 15-20 years has been such a bust. The industry thought that they could pretty much crank out useful and safe new molecules on demand if they just used a highly industrial system in which business efficiency and close links between R&D and marketing were the operative principles. Turns out, not so. So now the industry is coming back to the academic investigators, whose "inefficient" habits condemned them under the old regime. (Could it be that being really curious about how things work is actually a pretty good way to generate new scientific knowledge? Or that you really ought to try to understand basic mechanisms before you rush off to develop a new drug?)

This is of course good news for a University president frustrated with dropping NIH research budgets and the loss of tax revenues for higher ed., and who is looking to industry as the sugar daddy du jour. It is bad news for those of us concerned about the integrity of science and the huge conflicts of interest that arise when industry takes over the academic enterprise. The sad point is that there are, generally, pretty good ways to get the research done but also to maintain the integrity and separateness of the academic institution. To negotiate such a contract those on the U. side need a backbone, and a couple of other pieces of anatomical equipment best left unspecified in a family blog. In today's race to the pay window, too few universities seem to have the requisite anatomical parts. Even Harvard.

Friday, September 5, 2008

The September 3 issue of JAMA (subscription required) contains three commentaries on the drug industry, providing updates on medicine's relationships. The most newsworthy of them is probably Marcia Angell's (former editor of the New England Journal) analysis of the "broken system" of industry-sponsored clinical research. Dr. Angell concludes that we can no longer allow what most national academic-medicine organizations and leaders persist in assuming to be the bottom line-- that the drug industry will go on funding the clinical trials by which its own products are tested (and that the academic medical center can continue to rake in the resulting research grants plus whatever extras it can scarf up).

Things were not so bad, she recalls, before the 1980s. Then, the industry gave research grants to university investigators who planned and conducted the studies, had control over all the data, and decided on publication. The investigators, or their institutions, seldom had any financial relations with the industry apart from the research grant. Today, by contrast, investigators and their universities are both heavily in bed with the industry, investigators seldom even see the data in their entirety, and the industry staunchly defends a business model in which all data they pay for is their proprietary possession. Dr. Angell also identifies competition from commercial contract research organizations (CROs) and academic centers aping CROs to get the grants (see latest post on UNC selling its School of Public Health to the largest commercial CRO). The result: the problem of bias in research, with companies routinely suppressing data they do not like or else respinning negative studies to make them sound positive, and investigators meekly going along.

The only meaningful solution, says Dr. Angell, is to take the funding of clinical trials needed to assess new drugs out of industry hands, and create a new NIH institute to fund these trials. She repeats this recommendation from her book, The Truth About the Drug Companies, which I cited in giving the same recommendation in HOOKED. If anything, the accumulated data since her book first appeared in 2004 completely reinforce the need for this drastic step.

Though I agree with the recommendation to disconnect trial funding from individual drug companies, Dr. Angell might have said a bit more about what universities and academic leaders can do while waiting for this reform to happen. She seems to view the cozy financial relationships with industry as simply a given in today's world, though she does have some choice words to say about Stanford and its apparent willingness to look the other way as its chair of psychiatry, Dr. Alan Schatzberg, racked up more financial conflicts of interests per square centimeter than any academic in recent memory. (As Dr. Angell notes, when Stanford more recently announced that it had replaced Dr. Schatzberg as PI on his NIMH study of a drug in which he controlled $6M in stock, it claimed that it did so "to eliminate any misunderstanding"-- rather than because his being PI was an unacceptable conflict of interest and violated NIMH rules.) I would have liked to have heard some suggestions as to what the academic medical center could do today to start to better police this industry gravy train.

The core question is whether a CRO is truly independent because (as its defenders claim) it won't get research grants in the future unless it keeps a good reputation for high quality work, and it works for no single drug company; or is ultimately the creature of the industry because (as its critics claim and as I review in HOOKED) in the end, if you don't give drug firms the results they want to market their product, they'll take their business elsewhere. Lenzer gives many examples, mostly drawn from the world of academic CROs, that at least hint strongly at the existence of a decided pro-industry tilt that could seriously bias the research results. She also gives somewhat clearer evidence of a money-laundering operation--that the med school can form an academic CRO, the CRO can take money from a drug company, med school faculty can conduct the research, and when the study is published, all the publicity states that faculty at the med school discovered such-and-such, with nary a mention of the CRO or the company sponsorship.

What I took to be the major pearls from the paper--in the form of smoking guns, to mix metaphors--were:

One of the relatively few major trials demonstrating that serotonin-type (SSRI) antidepressants work in children and teenagers was the TAPS (Treatment of Adolescent Depression) study. This study was carried out by Duke University's academic CRO. The drug under study was Prozxac, made by Eli Lilly. The CRO does a fair amount of work for Lilly. Officially, the TAPS study was sponsored by the NIH. Lilly presumably simply donated the drug. However, TAPS has a number of design features that suggest a considerable bias in favor of Prozac. The worst was the fact that a couple of the arms of the trial were non-blind, when they just as easily could have been blinded, and the non-blind data accounted for a great deal of the total effect size atributed to Prozac. Lenzer noted another bias-suggestive feature--that the scoring system reported those who did better on the drug but omitted any mention of the number who did worse. She then tried to obtain the raw data, on how many did worse, from both the NIH and the principal investigator at Duke. The NIH refused, saying these data were in the possession of the PI. The PI and Duke refused to disclose those data. For a "publicly funded" study this seems strange behavior indeed.

Quintiles Transnational, based in North Carolina, is the world's largest CRO. Its founder and CEO, Dennis Gillings, recently donated $50 million to UNC's School of Public Health--now named the Gillings School of Global Public Health. UNC's chancellor, in writing to Gillings to thank him for the gift, stated that in return, the School would commit to "alignment of faculty behind focused programs," with the priority to be "new methodologies to speed clinical trials innovation." Now, this is odd. A school of public health as a rule is not in the pharmaceutical clinical trials business. If there is any school at the university that you'd expect would be looking at the importance of non-drug approaches to health problems, the School of Public Health would be it. Lenzer also noted that 8 current or former Quintiles executives now either head school programs or sit on advisory boards. Hmm--sounds like a CRO just bought a school of public health--and that UNC meekly handed it over.

This month's Of-All-the-Nerve Award goes to Steven Ferris, PhD of New York University; Douglas Galasko, MD of UC-San Diego, and Louis Kirby, MD of Provista Life Sciences in Phoenix.

Back in April, JAMA published a paper on ghostwriting, based on revelations from the Vioxx litigation and the resulting disclosure of internal Merck documents (see previous post, http://brodyhooked.blogspot.com/2008/04/jama-to-pharma-and-its-allies-enough.html). As an example of a ghostwritten paper with academic "guest authors," Ross et al. discussed in some depth a paper (Thal et al. 2005) listing these gentlemen as co-authors. The three awardees thereupon wrote an angry Letter to the Editor to JAMA denouncing their inclusion in the article as guest authors.

They insisted that all had had "substantial roles" in designing and carrying out the trial. They then admitted: "The paper was initially drafted by Merck coauthors in August 2003, after discussion of the results had previously taken place with Dr Thal and Dr Ferris in June and July 2003. Drs Thal, Ferris, and Kirby were formally approached about being coauthors on the paper and an associated abstract in September 2003. Each critically reviewed the complete statistical report and contributed to revising the final manuscript."

Having this conceded the major point of the accusation against them--that a Merck ghostwriter had in fact been the real "first author" and that they had seen the paper only after it was sent to them, virtually already completed, by the company--Ferris, Galasko, and Kirby went on to complain: "This unsubstantiated allegation of guest authorship raises questions about flawed methodology in the study by Ross et al. It is poor science to draw broad conclusions about pharmaceutical practices from limited and highly selective information. Moreover, neither the authors nor JAMA contacted the presumed guest authors for comments or clarification regarding this material or the allegation of guest authorship prior to publication. A change in author names does not necessarily mean that those added were not involved: such name changes occur frequently as research manuscripts are revised."

"Unsubstantiated"? Ross et al., in their reply to the Letter, remind the readers that as part of their analysis, they had compared the draft prepared by the Merck ghostwriter with the published article, and found only minor changes in wording and organization--so much for the "contributions" to revising the final manuscript.

It may be of some significance that in order to disclose all of their financial relationships with industry, Ferris et al. required 22 lines of fine print following their Letter.

I guess their theory is that the best defense is a good offense. When caught red-handed passing off a ghostwritten paper as your own work, attack the methodology of the expose.

(Thanks to Roy Poses at the Health Care Renewal blog for guiding my attention to this letter.)